DESCRIPTION (Applicant's Abstract): The main goal of this proposal is to develop new microarray-based high throughput single nucleotide polymorphism (SNP) analysis methods for the purpose of studying quantitative genetic factors underlying complex behaviors and diseases, such as individual's vulnerability for drug abuse and mental illness. Genome-wide SNP scanning has the potential to isolate the quantitative trait loci involved in complex disorders. It was estimated that a genomic region that contributes 5 percent or more to a disease could be localized to a 3 kb sequence with a SNP association analysis involving 500 individuals and 500,000 SNP markers across the whole genome. Since the Human Genome Project will soon generate the complete human genome sequence, and there are various public and private efforts to develop high-density human SNP markers, the framework required for genome-wide SNP scanning will quickly be established. However, none of the currently available SNP analysis methods can deal with such genome-wide high-density SNP scanning projects in a timely and cost-efficient manner. The proposed project aims to increase the output of a single operator to 400,000 SNP analysis per day using standard microarray laboratory equipment. The cost of SNP analysis for large-scale projects will also be reduced to around $0.01 for each SNP marker, with the exact cost depending on oligo synthesis. These goals represent an order of magnitude improvement over currently SNP analysis methods in both speed and cost. Foreseeable improvements in these methods have the potential of another 10-fold increase in throughput and further cost reduction. The new microarray array formats presented in this proposal will also be applied to a wide range of problems in functional genomics such as genomic DNA methylation analysis and differential display.